Postoperative Adjuvant Treatment in Women with Stage I Endometrial Cancer: A Retrospective Study

Objective To evaluate whether postoperative adjuvant treatment is beneficial for patient survival after surgery for early stage endometrial cancer (EC). We analyzed the outcomes of patients treated with radiotherapy, chemotherapy, or progestagen combined with other adjuvant treatments. Methods We analyzed the outcomes of patients treated with radiotherapy alone, chemotherapy alone, or progestagen treatment with other adjuvant treatments. Women without any adjuvant treatment after operation were used as controls. We retrospectively examined disease-free survival (DFS), overall survival (OS), and high-risk factors that affected the survival status of all patients who received different postoperative adjuvant therapies. Results In all 192 patients, the total relapse and mortality rates were 5.57% and 1.68%, respectively. Fourteen patients (7.29%) developed isolated local recurrence, and 2 patients died (1.04%) of recurrence during the follow-up period. The 5-year DFS and OS rates of all patients were 95.83% and 93.75%, respectively. No significant differences were observed in the 5-year DFS, 5-year OS, OS, or DFS among the four groups of patients with FIGO stage I endometrial cancer (P=0.9849, 0.7430, 0.9754, and 0.4534, respectively). The differences in the log-rank test results of the estimates of the 5-year DFS, 5-year OS, DFS, and OS of patients with different disease stages and different ages were all significant, but no differences were observed in these parameters among patients with varying degrees of differentiation. Histologic grade, CA125 level, ER and PR status, and adjuvant therapy had no significant effect on the DFS and OS of all patients according to univariate and multivariate regression analyses, but a significant effect on DFS and OS was found when the patients were stratified by age. Conclusion This retrospective study showed that adjuvant therapy after surgery was not significantly associated with improved DFS or OS in patients with early stage endometrial cancer. However, FIGO stage and age affected the survival of patients with stage I endometrial cancer.


Introduction
In China, 63,400 new cases of endometrial cancer and 21,800 deaths from this cancer type were reported in 2015 [1]. Adjuvant therapy is regarded as the backbone of treatment for advanced endometrial cancer, but the optimal strategy to prevent recurrence and improve survival outcomes is still controversial, especially for early stage endometrial cancer. Terefore, the selection of appropriate postoperative adjuvant therapy for patients with early stage endometrial cancer is challenging.
Lymphovascular space invasion (LVSI) is considered to be an independent prognostic factor for survival and recurrence, and it has been shown to be related to lymphatic metastasis [2][3][4]. Patients with low-risk and low-intermediate-risk factors do not need adjuvant treatment, as they would not derive any beneft. Moreover, the optimal adjuvant treatment for patients with intermediate-risk and high-intermediate-risk factors is still controversial. In recent years, many doctors have reconsidered using chemotherapy for high-intermediate risk (HIR) stage I endometrial cancer despite the insufciency of randomized data to support this. Te results of a Cochrane Collaboration meta-analysis suggested a small numerical beneft in PFS and OS after patients received platinum-based chemotherapy for endometrial cancer [5]. However, some doctors have expressed diferent viewpoints. According to a systematic review, adjuvant chemoradiotherapy had no advantage over radiotherapy alone for overall survival and failure-free survival in high-risk patients with FIGO stages I-II endometrial cancer [6]. Terefore, whether early stage high-risk patients can beneft from adjuvant chemotherapy is worthy of further exploration.
Te value of progestogenic agents in advanced endometrial carcinoma has been well demonstrated, while their role as adjuvant therapies in early stage endometrial cancer is somewhat contentious. Some studies have shown that adjuvant progestagen therapy can reduce recurrence and improve the survival rate of patients with early endometrial cancer. In the 1970s and 1980s, several small studies suggested a survival beneft from progestagen in patients with endometrial cancer [7]. However, in observational studies, progestagens have been demonstrated to have a limited role in preventing recurrence compared with control treatments [8].
Since then, researchers have paid little attention to adjuvant endocrine therapy for early stage endometrial cancer.
Terefore, the primary theme of this study was to retrospectively evaluate the oncologic outcomes and survival statuses associated with various postoperative adjuvant therapies and to assess the risk factors that afect the status of women with stage I endometrial cancer.

Patients.
We retrospectively reviewed patients treated for endometrial cancer at our hospital (one of the major tertiary referral hospitals in China) from 2006 to 2016, and 654 patients diagnosed with FIGO stages I-IV endometrial cancer were identifed. Te Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, approved this study (TJ-IRB20210737). After diagnosis, all patients underwent either laparoscopic, abdominal total hysterectomy, or bilateral salpingooophorectomy with or without pelvic/para-aortic lymph node dissection and pelvic washing. Two gynecologic pathologists reviewed and confrmed the pathologic specimens. All patients were diagnosed with stages I-IV endometrial cancer according to the revised FIGO staging criteria [9]. Surgical treatment was followed by adjuvant radiotherapy (RT) alone, chemotherapy (CT) alone, hormone therapy with other adjuvant treatments, or no further adjuvant treatment.

Adjuvant Terapy after Surgery.
Te selection of adjuvant therapy was at the discretion of the attending gynecological oncologist who managed the patient. Treatment of patients was performed according to international guidelines and included vaginal brachytherapy. Te chemotherapy regimen used at our institution during the study period was platinum-based chemotherapy, with paclitaxel (135-175 mg/m 2 ) and carboplatin (AUC � 5) given for two to four cycles every 3 weeks. Progestagen treatment was initiated 3-4 weeks after surgery or after other adjuvant treatments ended. Te medroxyprogesterone acetate (MPA) dose was 250-500 mg administered once per day. Tis treatment was continued for 1 year.

Follow-Up.
Follow-up examinations were performed at either our institution or at hospitals local to the patients. All patients were followed-up after the completion of comprehensive treatment every 3 months for the frst 2 years, every 6 months during the next 3 years, and then yearly thereafter during the study period. Te oncological status of patients at the last medical visit was also assessed and determined to be either remission, recurrence, or death.

Statistical
Analysis. SPSS 20.0 statistical software was used for the statistical analysis; the "survival" package was utilized to apply complete survival analysis to the rightcensored data, while the results were visualized with the "survminer" package. Te univariate comparison of the four groups was summarized by descriptive statistics and tested by Fisher's exact method. Te count data were expressed as N (%), and the chi-square test was used to analyze diferences between groups. All data are represented as the mean ± standard deviation (SD), and variance analysis was used to test for diferences between groups. Te log-rank test was used for single-factor analysis of OS or DFS, and the Cox proportional risk model was used for multifactor analysis. Te statistical signifcance threshold was P < 0.05.

Patients and Tumor
Characteristics. In all stage of EC patients, 339 patients were successfully followed-up, and 315 patients were lost to follow-up after treatment. Overall, 147 patients with advanced-stage disease (II-IV) were excluded from this study. Finally, 192 patients were enrolled in the retrospective analysis. Te women were then divided into four groups (A group (45.83%), nonadjuvant treatment; B group (5.73%), radiotherapy; C group (34.38%), chemotherapy; D group (14.06%), MPA alone or combined with chemotherapy or radiotherapy). Eleven patients and 66 patients received radiotherapy and chemotherapy, respectively. Twenty patients received adjuvant hormone therapy alone, and 7 patients received MPA combined with other adjuvant treatments (5 patients received chemotherapy and 2 patients received radiotherapy). Te remaining 88 patients did not receive adjuvant treatment after surgery ( Figure 1).
Te baseline characteristics of all patients are summarized in Table 1. Te median follow-up for all patients was 51 months (range: . No signifcant diference was found among the four groups in terms of age, histologic subtype, ER expression, or CA125 level in serum. A few patients were diagnosed with rare pathological types, such as adenocarcinoma (mesonephric-like), clear cell carcinoma, serous papillary carcinoma, mucinous papillary adenocarcinoma of the intestinal epithelium, and papillary adenocarcinoma (villous-tubular carcinoma subtype). Te proportions of these rare subtypes did not difer among the groups. In addition, we found that histologic grade, FIGO stage, and PR expression difered among the four groups (P � 0.0005, P � 0.0112, and P � 0.0064). Among 192 patients, 168 (87.5%) underwent pelvic lymphadenectomy, and 11.46% (22/192) underwent pelvic and para-aortic lymphadenectomy. No diference was found in the proportion of lymphadenectomy among the four groups (P � 0.9688 and P � 0.4211).

Survival Outcomes.
Te total relapse and mortality rates of all 192 patients were 5.57% and 1.68%, respectively. During the follow-up period, 14 patients (7.29%) developed isolated local recurrence, and 2 patients (1.04%) died of recurrence. Te 5-year OS and DFS rates of all patients were 93.75% and 95.83%, respectively. In this study, the log-rank test was used to test the signifcance of diferent treatments. No statistically signifcant diferences were observed in the 5year DFS, 5-year OS, OS, or DFS among the four groups of patients with stage I endometrial cancer (P � 0.9849, 0.7430, 0.9754, and 0.4534) ( Figure 2). Tis result suggested that adjuvant chemotherapy, radiotherapy, or hormone therapy + chemotherapy/radiotherapy after surgery did not improve the DFS or OS rates of patients with stage I endometrial cancer.

Te Clinical Factors Tat Afect Survival Status.
To assess the risk factors that afect the survival status of women with stage I endometrial cancer, we performed a univariate analysis of diferent variables. Te log-rank test (time series test) was used for the univariate analysis to analyze the impact of various factors on prognosis. Histologic grade, estrogen receptor status, progesterone receptor status, and CA125 level were not associated with significant diferences in DFS and OS (log-rank, P � 0.6946, 0.9199, 0.9347, and 0.3272), but patient age was associated with prognosis (log-rank, P � 0.0045 for DFS and 0.0003 for OS) (

Discussion
As China has become an aging society, the number of women who experience obesity and the incidence of EC have proportionally increased. EC has the strongest link with obesity, every 5 kg/m 2 increase in BMI associated with 54% increase in EC risk [10]. Obesity creates a proinfammatory milieu, which might contribute to endometrial cancer risk [11]. Approximately 80% of endometrial cancers are hormone receptor-positive endometrioid adenocarcinomas. Most endometrioid carcinomas are well to moderately diferentiated [12]. Te percentages of patients with G1-G2 and G3 were 89% and 11%, respectively. Te clinical data of this study are consistent with the literature and suggest that approximately 10% of endometrial cancers are type-2 (highgrade) lesions. Up to 40% of nonendometrioid endometrial cancers are mixed with an endometrioid component [13]. In our study, a few cases were diagnosed with rare pathological types, such as the endocervical type, clear cell carcinoma, mucinous papillary adenocarcinoma of the intestinal epithelium, the villous-tubular carcinoma subtype, and serous papillary carcinoma. Since the number of cases was small, it was difcult to evaluate the prognosis of these subtypes and their impact on the results of this study.
Whether adjuvant therapy should be administered after surgery for early endometrial cancer is still controversial. NCCN guidelines recommend that complementary radiotherapy or systemic therapy be considered if patients have potential high-risk factors, including age ≥60 years, deep myometrial invasion, and/or LVSI [14]. Patients with focal or substantial LVSI received diferent adjuvant treatments according to a three-tiered system that quantitates LVSI. In contrast, the presence of LVSI is associated with a high risk of mortality in patients with early stage well-diferentiated endometrial carcinoma [15]. Te Cancer Genome Atlas (TCGA)-typing for EC was proved as a tool for guiding treatment. But the data of TCGA typing in this retrospective study were missing, and we could not analyze the factor in our study. No diference was found in the survival rates between groups after a 5-year follow-up [16]. Te current retrospective study revealed no statistically signifcant differences in the 5-year DFS, 5-year OS, OS, or DFS across the four groups of stage I endometrial cancer patients. Similar results were observed in two randomized trials (GOG-99 and PORTEC-1) and a retrospective study, which suggested no overall survival advantage of adjuvant radiation in patients with stage I, high-intermediate risk cancer [17][18][19]. In contrast, 50% of the 192 patients presented to our hospital for secondary surgery or further follow-up treatment after their frst surgery, which was performed at other hospitals.
As the LVSI status of these patients was unknown, we could not evaluate this factor. In a few studies, researchers reported that adjuvant endocrine therapy may provide a beneft in terms of delaying recurrence or prolonging the survival of patients with early endometrial cancer [20]. However, most randomized trials of adjuvant progestagen therapy have failed to show any advantage in endometrial cancer, and data have even revealed that death due to cardiovascular disease tended to be higher in the progestagen group than in the control group [21][22][23]. Tese fndings are consistent with our results. In our study, carboplatin plus paclitaxel was adopted as postoperative adjuvant chemotherapy in many patients with stage I disease. Te data suggested that women gain little beneft from adjuvant chemotherapy, including women with high-risk factors, such as deep myometrial invasion and the serous or clear cell histologic type. Indeed, many studies have demonstrated that adjuvant chemotherapy for highrisk endometrial cancer does not improve survival rates [24,25]. However, the results of randomized trials have varied, and some previous studies have suggested that adjuvant chemotherapy after surgery is benefcial for early stage EC with HIR factors [26]. Furthermore, two retrospective studies showed that adjuvant platinum-based chemotherapy plus vaginal brachytherapy (VBT) achieved excellent results in high-risk early-stage endometrial cancer [27,28]. However, we were unable to confrm this result because this retrospective study contained no such cases.

International Journal of Clinical Practice
According to our retrospective observations, the differences in DFS and OS were signifcant between stage IA and stage IB. Tat is, even in early endometrial cancer, the FIGO stage still afects the DFS and OS of endometrial cancer patients. Moreover, age (<60 years and ≥60 years) was another factor infuencing the prognosis of patients with early stage endometrial cancer. Notably, according to both the univariate and multivariate analyses, ER status, PR status, CA125 level, histologic grade, and the type of adjuvant therapy did not afect PFS or OS in FIGO stage I endometrial cancer patients in our study, but age was associated with diferences in OS and PFS. Many physicians have verifed that the cancer antigen 125 (CA125) level, age older than 60 years, and depth of myometrial invasion >50% were signifcant factors for overall survival in a retrospective study [29]. Age >60 years (or > 50 years) and degree of diferentiation may be high-intermediate risk factors according to a systematic review of guidelines in the US [30].  Among all the factors analyzed in our study, age was the only indicator that independently afected OS and DFS in stage I endometrial cancer. Due to incomplete data on lymph node metastasis in this study, it was not possible to analyze this factor and its impact on survival status.
Te goal of adjuvant therapy in endometrial cancer is to reduce the risk of disease recurrence, and whether postoperative adjuvant therapy should be used for early endometrial cancer is controversial. Our results agree with the above fndings and suggest that postoperative adjuvant treatments are not associated with better OS or DFS in patients with either FIGO stage IA or stage IB endometrial cancer. All the above evidence seems to support the conclusion that women do not gain a survival advantage from postoperative adjuvant therapy after surgery for stage I endometrial cancer regardless of disease stage (IA and IB). Nevertheless, our study still has some shortcomings. Te main limitation of our study is that we included in our analysis with retrospective study nature. It is limited by its retrospective nature, the heterogeneity of the data and the reliance on clinical endometrial cancer data not originally collected for research purposes. We could only analyze the results from the follow-up data as the lack of some clinical data, such as LVSI and a high rate of loss to clinical followup. Additionally, it was limited by single-center experience and potential selection bias, which may limit its external validity. Our results may not represent the fndings of other hospitals.
Terefore, it is necessary to further discuss the benefts and disadvantages of adjuvant endocrine therapy, chemotherapy, and radiotherapy as well as the major risk factors for early endometrial cancer. In the future, it will be possible to achieve the goal of personalized treatment for individual patients.

Data Availability
Te data used to support the fndings of this study are included within the article.

Ethical Approval
Medical Ethics Committee of Tongji Hospital Afliated to Tongji Medical College of Huazhong University of Science and Technology approved the study (No: TJ-IRB20210737).

Consent
All study participants provided an informed written consent included the records of hospital. Te study was conducted ethically in accordance with the 2013 Helsinki World Medical Association Declaration.

Disclosure
Tis manuscript was previously preprinted on a third-party platform [31] and was not published under elsewhere. Te link is https://www.researchgate.net/publication/ 354917985_Ten-Year_Results_of_Postoperative_Adjuvant_ Treatment_In_Women_With_Stage_I_Endometrial_ Cancer.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
All authors have approved this manuscript. Peiying Fu and Haiying Sun have contributed equally to this manuscript.